The present invention relates to a process for obtaining (nitroxymethyl)phenyl esters of salicylic acid derivatives.
It is known in the prior art that the (nitroxymethyl)phenyl esters of the salicylic acid derivatives can be prepared by various synthesis processes. In the patent application WO 97/16405 the reaction of the acyl chloride of the acetylsalicylic acid with (nitroxymethyl)phenol is described. The (nitroxymethyl)phenol is prepared by a synthesis which comprises the following steps:
reaction of the phenol with HBr in organic solvent to obtain (bromomethyl)phenol, and
reaction of the (bromomethyl)phenol in organic solvent with AgNO3 with formation of (nitroxymethyl)phenol
The process based on the reaction between (nitroxymethyl)phenol and the acyl chloride of the acetylsalicylic acid shows the following drawbacks:
the (bromomethyl)phenol obtained in the first synthesis step is a chemically unstable and irritating compound;
the nitrating agent used in the reaction with (bromomethyl)phenol is a very expensive reactant;
the (nitroxymethyl)phenol is an unstable compound, which can easily decompose in an uncontrollable way; and it must be purified before the reaction with the acetylsalicylic acid chloride, furtherly increasing the production costs and requiring supplementary units in the production plant.
In conclusion the synthesis of above derivatives, by using the intermediate (nitroxymethyl)phenol, is difficult and expensive to be carried out on an industrial scale.
In PCT Patent EP 00/00353 in the name of the Applicant a synthesis process of nitroxy derivatives of formula (I) (see hereunder) is described, by submitting to nitration with AgNO3 (hydroxymethyl)phenyl esters of the acetylsalicylic acid, obtained by reacting the acid chloride with hydroxybenzaldehyde and reducing the aldehydic group to primary alcohol. Also this process, as the above mentioned uses silver nitrate as nitrating agent and therefore it is not much advantageous from an industrial point of view. Besides the process global yields are not high.
By using the teaching of the prior art, it is possible to obtain the salicylic acid nitroxyderivatives of formula (I) (see below) by reacting a (hydroxymethyl)phenyl ester of the acetylsalicylic acid with nitrating reactants based on nitric acid. However under the reaction conditions of the prior art the nitric acid produces undesired reactions, such as for example the nitration of aromatic substrata (ref. xe2x80x9cNitration: Methods and Mechanismxe2x80x9d, 1984 VCH ed., p. 269) and the oxidation of primary alcohols to aldehydes (ref. xe2x80x9cIndustrial and Laboratory Nitrationxe2x80x9d 1976 ACS publ., p. 156).
Therefore also said processes of the prior art are unable to solve the problem of the preparation on industrial scale of the nitroxyderivatives of the salicylic acid as above defined.
The need was felt to prepare nitroxy derivatives of (hydroxymethyl)phenyl esters of the acetylsalicylic acid by a process cheaper than those of the prior art both for the nitrating agent used and for the yields, and substantially without the drawbacks of the prior art.
An object of the present invention is a process for obtaining (nitroxymethyl)phenyl esters of the salicylic acid derivatives, compounds having the following formula (I): 
wherein:
R1 is the OCOR3 group; wherein R3 is methyl, ethyl or linear or branched C3-C5 alkyl, or the residue of a saturated heterocyclic ring having 5 or 6 atoms, containing hetero-atoms independently selected between O and N;
R2 is hydrogen, halogen, linear or branched when possible C1-C4 alkyl, linear or branched when possible C1-C4 alkoxyl; linear or branched when possible C1-C4 perfluoroalkyl, for example trifluoromethyl; mono- or di-(C1-C4)alkylamino;
preferably in (I) R1 is acetoxy and is in ortho position with respect to the carboxylic group, R2 is hydrogen; the oxygen of the ester group is bound to the aromatic ring substituted with the (nitroxy)methylene group in ortho, meta or para position with respect to the (nitroxy)methylene group; preferably the position is the meta one;
said process comprising the following steps:
a) reaction of a halide of a salicylic acid derivative of formula (I-A): 
xe2x80x83wherein Halxe2x95x90Cl, Br, and K and R1 and R2 have the above indicated meaning, with hydroxybenzylalcohol in the presence of a base, in an organic solvent, or in a mixture of water with a miscible or immiscible organic solvent with water, to give the compound (I-B) having the following formula: 
xe2x80x83wherein R1 and R2 are as above defined;
b) nitration of the compound (I-B) in anhydrous conditions, in an inert organic solvent, by a mixture formed by steaming nitric acid with an inorganic acid different from nitric acid or with an organic acid, or with the anhydride of one or two organic acids, to give the nitroxyderivative of formula (I).
c) recovery of the final product by adding water to the organic phase, separating the phases, drying and evaporating the organic phase.
In step a) the base can be an inorganic base, such as for example hydroxides, oxides, carbonates and bicarbonates of alkaline metals (sodium, potassium, lithium); or an organic base, for example a tertiary amine, for example aliphatic, cycloaliphatic, heterocyclic, heterocyclic aromatic, such as triethylamina, diisopropyl-ethylamine, N-methylmorpholine, diazaabicyclooctane, etc.
The organic solvent used in step a) can be an organic solvent miscible with water such as C1-C4 aliphatic alcohols, for example methanol, ethanol, isopropanol, n-butanol; or an organic solvent immiscible with water for example aromatic hydrocarbons such as toluene and xylene, chlorinated organic solvents such as methylene chloride, chlorobenzene, other solvents which can be used are aliphatic esters for example of C1-C4 acids with C1-C5 alcohols such as for example ethyl acetate and butyl acetate, etc.: aliphatic and cycloatiphatic ketones, such as C3-C12 for example acetone, methylketone, cyclohexanone, etc.
In step a) the reaction is carried out at a temperature in the range xe2x88x9220xc2x0 C., and +50xc2x0 C., preferably 0xc2x0 C.-20xc2x0 C., by using, with respect to the hydroxybenzylalcohol moles under reaction, an amount by moles of acid halide (I-A) in a ratio between 1 and 2, preferably between 1.2 and 1.5, and an amount by moles of base between 0.1 and 2, preferably between and 2.
The compound I-B) is recovered from the reaction mixture by addition of water and optionally, when the reaction takes place in an aqueous solvent or in a mixture of water with an hydrosoluble organic solvent, by addition of an organic solvent immiscible with water, such as ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried, evaporated and the product is recovered. If necessary, the compound can be purified by crystallization from solvents such as for example n-hexane, n-heptane, ligroin, toluene, methanol, isopropanol, diisopropylether, etc or their mixtures. Generally the yields are higher than 80%.
In step b) the nitration reaction is carried out at a temperature in the range xe2x88x9220xc2x0 C. and +40xc2x0 C., preferably from 0xc2x0 C. to 20xc2x0 C.; the used amount by moles of nitric acid is in a ratio between 1 and 6, preferably 1 and 3, with respect to the moles of the hydroxyester (I-B); the amount by moles of organic or inorganic acid different from nitric acid, or of anhydride as above defined, is in a ratio comprised between 0.5 and 6, preferably between 1 and 3 with respect to the moles of the compound (I-B).
The inorganic acid different from nitric acid is for example sulphuric acid; the organic acid is for example methansulphonic acid, trifluoromethansulphonic acid, trifluoroacetic acid, trichloroacetic acid, acetic acid; the organic acid anhydride is for example acetic anhydride, trifluoromethansulphonic anhydride, trifluoroacetic anhydride, trichloroacetic anhydride, etc., or mixed anhydrides such as for example trifluoroacetic-trifluoromethansulphonic anhydride, etc.
The inert organic solvent used in step b) is a solvent which has boiling point lower than 200xc2x0 C. at atmospheric pressure and it can be a chlorinated solvent, such as for example dichloromethane; or a nitroalkane such as for example nitromethane, or an aliphatic or cycloaliphatic ether such as for example methylterbutylether, tetrahydrofuran, etc.; an ester for eaample ethyl acetate; or an aliphatic or aromatic nitrile such as for example acetonitrile, benzonitrile.
The solvent volume is not critical, generally the volume is comprised betwen 1 and 20 times with respect to the amount by weight of hydroxyester (I-B) under reaction.
When the nitration in step b) is carried out in the presence of an organic anhydride as above defined, preferably the anhydride is first mixed with the hydroxyester (I-B) and then the resulting mixture is added to the nitric acid solution in the inert organic solvent.
Preferably the used organic anhydride is acetic anhydride.
In step c) it is possible to recrystallize the obtained compound by using solvents such as for example n-hexane, n-heptane, ligroin, methanol, isopropanol or their mixtures.